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Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia

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Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia biomedicines Review Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia Motoki Eguchi 1, Yosuke Minami 1,*, Ayumi Kuzume 1,2 and SungGi Chi 1 1 Department of Hematology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan; [email protected] (M.E.); [email protected] (A.K.); [email protected] (S.C.) 2 Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, Kamogawa 296-8602, Japan * Correspondence: [email protected]; Tel.: +81-4-7133-1111; Fax: +81-7133-6502 Received: 11 June 2020; Accepted: 16 July 2020; Published: 24 July 2020 Abstract: FLT3-ITD and FLT3-TKD mutations were observed in approximately 20 and 10% of acute myeloid leukemia (AML) cases, respectively. FLT3 inhibitors such as midostaurin, gilteritinib and quizartinib show excellent response rates in patients with FLT3-mutated AML, but its duration of response may not be sufficient yet. The majority of cases gain secondary resistance either by on-target and off-target abnormalities. On-target mutations (i.e., FLT3-TKD) such as D835Y keep the TK domain in its active form, abrogating pharmacodynamics of type II FLT3 inhibitors (e.g., midostaurin and quizartinib). Second generation type I inhibitors such as gilteritinib are consistently active against FLT3-TKD as well as FLT3-ITD. However, a “gatekeeper” mutation F691L shows universal resistance to all currently available FLT3 inhibitors. Off-target abnormalities are consisted with a variety of somatic mutations such as NRAS, AXL and PIM1 that bypass or reinforce FLT3 signaling. Off-target mutations can occur just in the primary FLT3-mutated clone or be gained by the evolution of other clones. A small number of cases show primary resistance by an FL-dependent, FGF2-dependent, and stromal CYP3A4-mediated manner. To overcome these mechanisms, the development of novel agents such as covalently-coupling FLT3 inhibitor FF-10101 and the investigation of combination therapy with different class agents are now ongoing. Along with novel agents, gene sequencing may improve clinical approaches by detecting additional targetable mutations and determining individual patterns of clonal evolution. Keywords: acute myeloid leukemia (AML); FMS-like tyrosine kinase 3 (FLT3); quizartinib; gilteritinib 1. Introduction FMS-like tyrosine kinase 3 (FLT3) is classified as a type 3 receptor tyrosine kinase, along with KIT, FMS, and PDGFR [1–3]. FLT3 is composed of an extracellular region consisting of five immunoglobulin-like domains, and an intracellular region consisting of a juxtamembrane (JM) domain, two tyrosine kinase (TK) domains, and a C-terminal domain. FLT3 is expressed in normal hematopoietic stem cells and progenitor cells, and is dimerized upon binding with either membrane-bound or soluble FLT3 ligands (FLs) produced by bone marrow stromal cells, which subsequently causes the phosphorylation and activation of tyrosine residues in the activation-loop (A-loop) [4,5]. Phosphorylated FLT3 activates multiple intracellular signaling pathways involved in the survival, proliferation, and differentiation of hematopoietic stem cells, such as RAS/MAPK, PI3K/Akt/mTOR, and JAK/STAT5 [6–9]. Since FLT3 is frequently expressed in leukemic cells, FL stimulation induces proliferation and inhibits apoptosis in these cells [10,11]. In 1996, an internal tandem duplication in the JM domain-encoding region of FLT3 (FLT3-ITD) was identified in acute myeloid leukemia (AML) cells [12]. Thereafter, several types of mutations, including point mutations, deletions, and insertions Biomedicines 2020, 8, 245; doi:10.3390/biomedicines8080245 www.mdpi.com/journal/biomedicines Biomedicines 2020, 8, 245 2 of 21 have been detected around the D835 residue in the TK domain (FLT3-TKD) [13]. FLT3-ITD and FLT3-TKD mutations were observed in approximately 20 and 10% of AML cases, respectively [14–16]. Although both FLT3-ITD and FLT3-TKD are gain-of-function mutations, the upregulation of STAT5 was only observed in FLT3-ITD cell lines (32D/ITD) [17]. STAT5 positively regulated Pim-1, which eventually activated mTOR and Mcl-1, which consequently conferred resistance to Akt inhibition in FLT-ITD cell lines [18]. An experiment using transgenic mice with FLT3-ITD-positive hematopoietic stem cells revealed the clear promoting effects of nuclear factors in activated T-cells (NFATC1), a family of inflammatory transcriptional factors, on FLT3-ITD-driven precursor cell expansion and resistance to FLT3 inhibitors [19]. Recent studies suggest that circulating MYBL2, encoded by the cell-cycle checkpoint gene MYBL2, is detected in AML patients with FLT3-ITD mutations and is closely related to mutant FLT3 expression as well as to tumor cell activity [20]. Unlike FLT3-ITD consistently upregulating JAK/STAT signaling, FLT3-TKD enhance SHP1 and SHP2 activity that negatively regulate JAK signaling [21,22]. This may at least partially explain why FLT3-ITD showed more potent myeloproliferative advantages than those of FLT3-TKD in a mouse model [23,24]. The dual mutation of FLT3-ITD and -TKD (FLT3-ITD-TKD) has been found in a small population. A recent study showed that FLT3-ITD-TKD has the ability to activate STAT5, resulting in Bcl-x and RAD51 upregulation that accounts for drug resistance [25]. Since FLT3 mutations are frequently detected in AML and are associated with poor prognosis, this gene is considered a promising molecular target for AML [26,27]. It has been 20 years since abnormalities in the FLT3 were first discovered, and the application of FLT3 inhibitors in clinical settings in Japan, Europe, and the United States has resulted in a paradigm shift in the treatment of FLT3-mutated AML. However, resistance to FLT3 inhibitors has also been reported concomitantly. Mechanisms of the resistance and strategies to overcome it have been vigorously studied and ever-reviewed [28–30]. Along with the comprehensive understanding of pathologic FLT3 signaling and the acquired alterations responsible for drug-resistance, non-FLT3 abnormalities that may be closely associated with leukemic clone evolution are revealing its importance, suggesting new approaches. In this review, we summarize our current understanding of resistance to FLT3 inhibitors and discuss the strategies for overcoming this issue. 2. Prognostic Impact of FLT3 Mutations FLT3-ITD mutation has been recognized as one of the major adverse prognostic factors with nearly twice the increase in hazard ratio [31]. As mentioned in the European LeukemiaNet (ELN) recommendations [27], high allelic burden (generally indicating 50% or more) of FLT3-ITD (FLT3-ITDhigh) is consistently associated with worse prognosis [32–34]. On the other hand, the low allelic frequency of FLT3-ITD (FLT3-ITDlow) concomitant with NPM1 mutation possibly leads to favorable prognosis [35], though it has been fraught with controversy [36–38]. FLT3-ITDhigh with wild type NPM1 and FLT3-ITDlow with mutated NPM1 are classified as intermediate-risk [27]. Unlike FLT3-ITD, the prognostic significance of FLT3-TKD has not been determined [32,39]. With the development of potent FLT3 inhibitors, better clinical outcomes would be expected, especially in patients with FLT3-ITDhigh. Indeed, previously untreated FLT3-ITDhigh patients who received intensive chemotherapy with sorafenib, a FLT3 inhibitor, showed no significant but seemingly better relapse-free and overall survival than those with FLT3-ITDlow AML [34]. It is not fully known if the FLT3 allelic burden affects the properties in acquiring resistance to FLT3 inhibitors. However, given a certain somatic mutation will belong to a single clone, a larger proportion of mutant FLT3 allele may link to less divergent leukemic clones and vice versa, which theoretically affect drug sensitivity, relapse rates and eventually survival rates. Zhang and his colleagues graphically displayed the clonal evolutions of two individual cases; one for a single clone with a high frequency of FLT3-TKD that later relapsed with an additional mutation within the same clone and the other for complex clones not associated with first-detected FLT3-ITD mutation with low frequency [40]. The prognostic impact of FLT3 mutations and its allele frequency possibly be changed in the era of FLT3 inhibitors. Biomedicines 2020, 8, 245 3 of 21 3. Classification of FLT3 Inhibitors by Its Pharmacodynamics As first-generation FLT3 inhibitors, existing TK inhibitors such as tandutinib (CT53518), lestaurtinib (CEP-701), sunitinib (SU11248), midostaurin (PKC412), and sorafenib (BAY 43-9006), which can effectively inhibit FLT3 kinase have been studied [41–45]. Thereafter, the compounds with higher selectivity and inhibitory activity were identified. Gilteritinib (ASP2215), quizartinib (AC220), and crenolanib (CP868596) were developed as second-generation FLT3 inhibitors [46–50]. These FLT3 inhibitors are roughly classified into two types (i.e., type I and type II) based on their binding mode to FLT3 molecules. The conformation of the three amino acid residues Asp–Phe–Gly (DFG) in the A-loop of the FLT3 molecule is altered in accordance with the phosphorylation status of the tyrosine residue, which leads to the formation of an active DFG-in conformation or an inactive DFG-out conformation [51–53]. Type I inhibitors bind to the ATP-binding site and its vicinity, and subsequently bind with molecules in both DFG-in and DFG-out conformations. Since the molecular homology of various TKs is high and the ATP-binding sites are highly conserved among kinases, type I inhibitors are often less selective. In contrast,
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